Steroid derivatives



United States Patent ()fiice 3,352,854 Patented Nov. 14, 1967 ABSTRACT OF THE DISCLOSURE This invention relates to fusidic acid derivatives of the formula wherein. C is selected from the group -consisting of /H n o o o and 0 and C is selected from the group consisting of C=O and and intermediates utilized in the preparation thereof. The compounds of this invention possess androgenic activity.

This invention relates to and has as its object the provision of new physiologically active steroids, novelmethods for their production and new intermediates useful in said preparation. More particularly, this invention relates to steroid derivatives represented by the formula Cd CH.

wherein C is --C=O,

H 01 -C or 0 J a O -acy1 and C 7 is C O, 0].

The preferred acyl radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tertpentanoic acids), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acids), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and flphenylpropionic acids), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The novel compounds of this invention are pharmacologically active substances that possess anti-androgenic activity (i.e., they can be utilized in the treatment of such conditions as hyperandrogenic acne). They are also useful as anti-estrogenic and anti-gonadotrophic agents.

The compounds may be formulated for such administration, the concentration and/or dosage being based on the activity of the particular compound and the requirements of the patient.

Some of the final products of this invention are prepared by the process of this invention which entails a number of steps beginning with 4a,8,14-trimethyl-l8- nor-5a,8a,9/3,14fi-androstane-3,11,17-trione as starting material. This starting compound may be prepared by deactoxylating and epirnerizing 4a,8,l4-trimethyl-16[i hydroxy-18-nor 5a,8a,9B,13a,14B androstane 3,11,17- trione 16-acetate by refluxing this compound in the presence of glacial acetic acid and zinc dust.

In the first step of the novel process of this invention, the starting material is ketalized as by treatment with ethylene glycol in an acid medium at elevated temperatures (e g., under reflux conditions) to yield a mixture of 3,17-bisethylenedioxy-4a,8,14-trimethyl-18-nor 5a,8ot,9[3, 14,8-androstane-11-one and 3,11,17-trisethylenedioxy-4a, 8,14-trimethyl-l8-nor-5a,8a,9 8,13u,14,6-androstane. It is to be understood that propylenedioxy derivatives may also be obtained when propylene glycols such as 1,3-propylene glycol or 1,2-propyleneglycol are utilized in lieu of ethylene glycol in the ketalization processes of the invention. The mixture of these androstanes may be separated by fractional crystallization or chromatographic separa- -tion.

The compound .3,17-bisethylenedioxy-4a,8,14-trimethyl-18-nor-5a,8a,9,8,14[3-androstane-1l-one may then be reduced as by treatment with lithium aluminum hydride to yield the new intermediate 3,17-bisethylenedioxy-1lustane. Further, a new intermediate 4a,8,l4-trimethyl-11avhydroxy-l8-nor-5ot,8m,9[i,14fi-androstan-3,17 dione may be prepared by hydrolysis of 3,17-bisethylenedioxy-l1ahydroxy-4a,8,14-trimethyl-18 nor 5a,8oc,9,B,14,B-andr0- stane with a weak carboxylic acid (e.g., acetic acid).

This new 3,17-dione intermediate may then be dehydrated in the presence of an aromatic base and an inorganic acid chloride such as pyridine and thionyl chloride at a temperature of from -5 to 15 C. to form a A compound of this invention, 4u,8,14-trimethyl-18- nor-5123a,14fl-androst-9(l 1 )-ene-3,l7-dione. The bisketal of this A compound may also be prepared by dehydrating the new 3,17-bisketal androstane of the invention in a similar manner. Thus, 3,17-bisethylenedioxy-11ahydroxy-4a,8,14-trimethyl-18 nor 5u,8a,9fl,l4fi-androstane may be dehydrated to form the corresponding 3,17- bisethylenedioxy-4a,8,14-trimethyl 18 nor- 5a,8u,l4,8- androst-9(ll)-ene. Hydrolysis of this latter intermediate will also give the aforementioned compound of this inven tion, 4u,8,14-trimethyl-l8-nor-5u,8a,14/3 androst 9(11)- ene-3,l7-dione.

Utilizing the same procedures set forth hereinabove and starting with 4a,8,14-trimethyl-l8-nor-5a,8a,l4;3 -androstane-3,11,17-trione as the starting material, the preparation of WhlChlS disclosed in US. patent application Ser. No. 399,339, filed Sept. 25, 1964 now abandoned, in lieu of 4u,8,14-trimethyl-18-nor 5a,8a,9,8,14j8 androstane-3, 11,17-trione, 40:,8,14-trimethyl-18-nor-5a,8a,14}3-androst- 9(11)-en-3,17-dione is again obtained as an end product. In addition, the corresponding 90: intermediates are also formed in this procedure. Intermediates which are formed are 3,17-bisethylenedioxy-4u,8, 14-trimethyl-l 8-nor5 :,811, 14fi-androstane-11-one; 3,17 bisethylenedioxy 11,8 hydroxy-4u,8,14-trimethyl-18-nor-5u,8m,14/3 androstane; 3, 17-bisethylenedioxy-4a,8,14-trimethyl-18-nor oc,80z,14,6- androst-9(11)-ene and 4a,8,l4-trimethyl-1lfl-hydroxy-IS- nor-5a,8a,l4fl-androstane-3,17-di0ne..A novel product 3,

17-bisethylenedioxy-4a,8,14-trimethyl-l8-nor 5u,8oz,13a,'

14B-androstane-1l-one is formed during the ketalization of 40,8,14-tIlI1'l6thYl-18-I1OI-50t,80t,14B8.nd1'OStaIl6-3,11,17- trione. This product when hydrolyzed, reduced and dehydrated in the manner set forth herein will give corresponding 13a derivatives, such as 3,17-bisethylenedioxy- 11, 3-hydroxy-4u,8,14 trimethyl-lS nor 5a,8a,13ot,14flandrostane; I 11 B-hydroxy 4a,8,14-trimethyl-18-nor-5a,8ix, 13 a,14B-androstane-3,17-dione; 3,17-bisethylenedioxy-4a, 8,14-trimethyl-18-nor-5a,8a,13a,14B-androst 9(11) ene and 4u,8,14-trimethyl 18 nor 5m,8a,13a,145 androst- 9(1l)-en-3,17dione. Hydrolysis of 3,17-bisethylenedioxy- 40:,8,14-trimethyl-18-nor-5a,8a,1304,145 androstane 11- one will also form 411,8,14-trimethyl-18-nor-5a,8u,13a, 14B-androstane-3,l1,17-trione.

Further, the acyloxy derivatives of the A901) compounds of the invention are prepared by starting with the compound 3a-acetoxy-4a,8,14-trimethyl-18-nor-5u,8a,9fi,1413- androstane-11,17-di0ne. This compound can be ketalized by reacting it with ethylene glycol in a manner substantially as hereinbefore set forth, The reaction mixture will contain 3a-acetoxy-17-ethylenedioxy-4a,8,l4-trirnethyl-l8- nor-5a,8oz,9fi,HB-androstane-l1 one and a new intermediate 3ot-acetoxy-11,17-bisethylenedioxy 4a,8,14 trimethyl-18-nor-5a,8a,9[3,13,l4B-androstane. It has been discovered that this latter new intermediate may be hydrolyzed by reacting it with a weak acid, e.g., acetic acid, to form 3a-acetoxy-4a,8,l4-trimethyl-l8-nor-5a,8a,9 8,13a, l4B-androstane-l 1,17-dione. 3 a-acetoxy-17-ethylenedioxy- 411,8, 14-trimethyl-18-nor-5a,8a,9fi,14/3-androstane-11 one may be reduced by known methods to form the intermediate l7-ethy1enedioXy-3a,lla-dihydroxy4a,8,l4 trimethyl-l8-nor-5a,8a,95,14,6 androstane. Acylation, hydrolysis and dehydration of this intermediate by procedures set forth herein will yield 3a-acetoxy-17-ethylenedioxy-l1u-hydroxy-4u,8,14*trimethyl-18 nor 5u,8a,9B, 14,8-androstane; 3at-acetoxy-1la-hydroxy 4a,8,14 trirnethyl-l8-nor-5a,8m,9fi,14B-androstane-l7-one; 3a acetoxy-l7-ethylenedioxy-4u,8,l4-trimethyl-18 nor 5a,8a, l4fi-androst-9(l1)-ene; and a final product 3a-acetoxy- 4a,8,l4-trimethyl-l8-nor-5a,8a,14B-androst 9(11) ene- 17-one. Following the procedure set forth above, but utilizing 3B-acetoxy-4 8,14-trimethyl-l8-nor 5a,8a,9fi, 14fl-andros-tane-1l,17-dione in lieu of the 3a-acetoxy-4a, 8,14-t1imethyl18-nor-5ot,8a,9fi,14/3 androstane 1'l,'l7- dione, the corresponding 35 derivatives are obtained.

The starting material 3p-acetoxy-4a,8,14-trimethyl-l8- HOT-50c,8oc,9fi,14,8-8.ndf0StaIl6-11,17-Cll01'i6 is prepared by the treatment of 3,8,16,3-diacetoxy-11a-hydr0xy-4a,8,14- mmethyl-18-nor-5u,8a,9;8,l3a,14fl-cholest 17(20)'- ene- 21-oic acid with a methylating agent, e.g., ethereal diazomethane, to give the corresponding methyl ester. This compound when treated with ozone at a reduced temperature in a suitable solvent, e.g., -70 C. in methylene chloride containing a trace of pyridine is converted to 3/3,16fldiacetoxy-4a,8,14 trimethyl-l8 nor 5a,8a,9fl,13oc,14}9- -androstane-1l,17 dione. This compound can be deacetoxylated and epimerized in one step by heating in the presence of glacial acetic acid and zinc dust to give 3/5- acetoxy-4oc,8,14-trin1ethyl-18-nor 5u,8a,9,8,14[3 androstane-11,17-dione.

The final products 3a-acetoxy-4a,8,l4-trimethyl-18-nor- 5 02,801, -androst-9( 1 1 -ene-17-one and 3u-ace-toxy-4a,8, 14-trimethyl-18-n0r-5a,8a,13a,14B-androst-9(11)-ene 17- one may also be prepared by starting with the material 30cacet0Xy-4a,8,14-trimethyl-18-nor-5oa,8ot,14fl androstane- 11,17-dione, the preparation of which is disclosed in US. patent application Ser. No. 399,339, filed Sept. 25, 1964. Following the same procedure utilizing the starting material 3fl-acetoxy-4u,8,14-trimethyl-18-nor-5a,8a,145 androst-ane-11,17-dione, which is prepared by the epimerization and reacetylation of 3fl-acetoxy-4a,8,14-trimethyl-18- nor-5a,8ot,9 3,14fi-androstane-11,17-dione leads to the cor responding 35-acetoxy-4a,8,14-trimethyl-18-nor Sa,8a, l3a,14/3-androst-9(1l)-ene-17-one and 3fi-acetoxy-4a,8, 14-trimethyl-18-nor-5a,8a,l4fl-androst-9(1l)-ene-17 one, which are obtainable utilizing substantially the same procedures as those described above for the preparation of 3a-acetoxy-4a,8,14-trimethyl-18-nor-5a,8a,14,8 androst- 9(11)-ene-17 one and the 13m isomer. Intermediates formed utilizing 3a-acetoxy-4a,8,14-trimethyl-18-nor-5a, 8a,14B-androstane-11,17-dione and 3;5-acetoxy-4a,8,14-trimethyl-18-nor-5a,8a,14/3-androstane-11,17-dione as starting materials are, respectively,

3a-acetoxyl'7-ethylenedioXy-4oc,8, l4-trimethy1-18-nor- 5u,8a,14B-androstane-1l-one;

3 fi-acetoxyl7 -ethylenedioxy-4a,8, 14-trimethyl-l 8-nor- 5a,8ot,14B-androstane-1l-one;

3 3-acetoxy- 17 -ethylenedioxy-4u,8, l4-trimethyl-18-nor- 5oz,8u,13a,145-androstane-1l-one;

17-ethylenedioXy-3 a,1 1B-dihydroxy-4a,8,14-trimethyl- 18-I10I-5u,8ot, 14fl-androstane;

17-ethylenedioxy-3 13,1 1/3-dihydroxy-4a:,8,14-trimethyl-18- nor-5a,8a,14,8-androstane;

17-ethylenedioxy-3 oc,1 1 B-dihydroxy-4a,8, l4-trimethyl 18-nor-5a,8a, 13 a, l4fl-androstane;

17-ethylenedioxy-3 pt, 1 lfi-dihydroxy-M, 8,14-trimethyl-18- nor-5a,8oc, l3 nc,l4,B-androstane;

3 a-acetoxy-17-ethylenedioxy-l 1fl-hydroxy-4a,8, 14-

trimethyl-l 8-11OI-50c,80c, 14B-androstane;

3 fi-acetoxy- 17 -ethy-lencdioxy-1 1 fl-hydroxy-4 8,14-

trimethyl- 1.8-nor-5 oz,8ot, 14,8-androstane;

3a-acetoxy-17-ethylenedioxy-l lB-hydroxy-.4a,8,14 -trimethyl-18-nor-5a,'8n,l 3a,14fl-androstane;

3 fi-acetoxy- 17-ethylenedioxy-l 118-hydroxy-4a,8,14-trimethyl-18-nor-5u,8a,13 a,14,8-androstane;

3 a-acetoxy-17-ethylenedioxy-4m,8,14-trimethyl-18-nor- 511,8, 14/8-androst-9 1 1 -ene;

3 fl-acetoxy- 17 -ethylenedioxy-4a,8, 14-trimethyl-l S-nor- 5u,8a,14/3-androst-9(l1)-ene;

Sa-acetoxy-l 1 3-hydroxy-4e,8,14-trimethyl-l8-nor- 5oz,8oc, 14/8-andr0stane-1 7-one;

3fl-acetoxy-115-hydr0xy-4a,8,14-trimethyl-18-nor- 5 0:,8a, 14/3-and-rostane-17-oi1e;

BB-acetoxy-l1p-hydroxy-4a,8,14-trimethyl-18-nor- 50:,802, 13 a, 14B-androstane17-one;

3 ot-acetoxy-17-ethylenedioXy-4a,8, l4-trimethyl-l 8-nor- 50c,8ot,13oc,14fi-.andr0St-9( 1-1)-ene;

3 fi-acetoxy- 17 -ethylenedioxy-4,a,8,14-trimethyl- 1 8-nor- 5m,8a,13a,14fi-androst-9(l1)-ene.

The processes of this invention may be best illustrated by the following:

Ketalization Reduction/ l Hydrolysis {Acylation l J. O OH H\/ H l I l K\/ U U R R In \I/ v l Deketalizatlon \gehydration O o t OH H H i \:/l (\;/\5/ R R1 v I v1 \Dehydration /6eketalization VII wherein R is 0 0,

In addition, hydrolysis of 3ozor 3B-acetoxy-17-ethylenedioxy-4a,8, 14-trimethyl-1 8-nor-5 11,8, 13 u,14,8-androstanell-one in a weak acid such as acetic acid gives the new compounds 3aand 3fi-acetoxy-4a,8,14-trimethyl-18-nor- 5w,8a,13a,14fi-androstane-1 1,17-dione, respectively.

The invention may be illustrated by the following examples. All temperatures are in degrees centigrade unless otherwise stated.

Example 1 .M ethyl 3,9,16B-diacetoxy-1Ia-hydroxy-4u,8, l4-trimethyl-18-n0r-5a,8a,9 3,13a,14,8-ch0lest 1 7 (20) ene-21-oate A solution of 3 8,16,6-diacetoxy-1la-hydroxy-4a,8,14- trimethyl-18-nor-5a,8a,9,8,13a,14,8-cholest 17 (20) ene- 21-oic acid in ether is treated with excess ethereal diazornethane. Evaporation of the solvent gives methyl 3 5,166- diacetoxy-lla-hydroxy-4a,8,14-trimethyl-18 nor 5a,8a, 9B,13a,14fl-cholest17(20)-ene-21-oate.

Example 3.3B-acet0xy-4a,8,14-trimethyl-18-n0r 5 a,8a, 95,14,8-andr0stane-11,17-di0ne A solution of 3B,16B-diacetoxy-4u,8,14-trimethyl 18- nor-5a,8a,9[3,13m,l4,B-andr0stane-l1,17 dione in glacial acetic acid containing zinc dust Was refluxed for 3 hours. After cooling, the solution was filtered and evaporated in vacuo togive 3B-acetoxy-4a,8,14-trimethyl-18 nor-5a,8a,

9,8,14fi-androstane-l1,17-dione.

A solution of 5% ethanolic potassium hydroxide is heated to reflux under a blanket of helium. To the hot solution is added 3fi-ac'etoxy-4a,8,14-trimethyl-l8-nor 5a,8a,9;3, 14fl-androstane-11,17-dione and the mixture is refluxed for 3 hours under helium. The reaction mixture is then acidified with 20% sulfuric acid, cooled and diluted with water. After evaporation of the alcohol, the aqueous residue is extracted with methylene chloride and the methylene chloride solution washed with water until neutral, dried over magnesium sulfate and evaporated to give Sfl-hydroxy-4oc,8,l4-trirnethyl-l8-nor-5a,8a,14,8-androstane 11, 17-dione.

Example 5.3;3-acet0xy-4a,8,14-trimethyl-18-n0r 5a,8oc,

14,8-andr0stane-11J7-di0ne I I A solution of 3fi-hydroxy-4u,8,l4- trimethyl-l8-nor-5a, 8a,14fi-androstane-11,17-dione in a mixture of pyridineacetic anhydride (2:1) is left overnight at room temperature. The excess acetic anhydride is decomposed with water and the mixture evaporated to give 3fi-acetoxy-4a,8,l4- trimethyl-l8-nor-5a,8a,l4p-androstane-11,17-dione.

Examples 6 to 11 Substantially following the procedure of Example 5 but utilizing molar equivalents of the compounds set forth in Table A in lieu of 3,8-hydroxy-4a,8,14-trimethyl-18-nor-5w, 8u,l4fl-androstane-11,17-dione, the products obtained are as indicated. 7

Examples 12 to 14 Following the procedure, of Example 5 but utilizing molar equivalents of the reactants of Table B in lieu of acetic acid and 17-ethylenedioxy-3a,11a-dihydroxy-4u,8, 14-trimethyl-18-nor-5a,8a, 9,8,14B-androstane in place of 3e-hydroxy-4e,8,14-trimethyl-18-nor 5a,8,a,14fi androstane-1l,17-dione, the products obtained are as indicated.

TABLE B Ex. Reaetant Product .12- Propionic anhy- .3a-propiony1oxy-17-ethylenedioxy-lladride. 1 hydioxy-4u,8,14-trimethy1-18-nor-5a,8a, 9fl,14B-androstane.

13.... Bcnzoie anhy -3a-benaoyloxy l7-ethy1enedioxy4ladlydride. droxy-4u,8,14-trirnethyl-l8-nor-5a,8a,9fl,

14,8-androstane. 14. Phenylaceti o Ba-phenylacetoxy 17-ethylened1oxy 11aanhydride. hydroxy-4a,8,14-minethyldB-nor-fiafia, 95,14,5-andrcstane.

Example 15.--3,1 7-bisethyle1zedioxy-4u,8,14-trimetlzyl-18- nr-a,8a,14fl-androstane-11-pne and 3,1 7 .-bisethy1enedioxy 4u,8,14 trimethyl 1-8 nor ia,8a,13a,14 3-androstane-J] -one A mixture of 4.68 mg. of 4a, 8,14-trirnethyl-18mor-5a, 8u,14[3- androstane-S,11,17-trione, 117 m1. of ,dry benzene, 23 ml. of ethylene glycol and 46 ingot p-toluenesultonic acid monohydrate is stirred and refluxed for 40 hours. The water termed during the reaction is removed by a Dean-Stark moisture trap and containing a calcium carbide thimble. The yellow solution thus formed is then dilutedwith chloroform and washed with-% sodium bicarbonate and then with water and evaporated, in vacuo. The residue on crystallization from acetone-hex ane gives 302 mg. of 3,17-bisethylenedioxy-4u,8,,14-trimethyl 18 nor 5a,8a,1418-androstane-1l-one .having a melting point about 182-484 (3., {0113 -i32 (chloroform),

Aggy} 5.91 m

Analysis.-Calcd for C H O (418.55): C, 71.74;*H,

. 9.15..Found: C, 71.60; -H, 9.07.

The mother liquor is evaporated and the residue is plate chromatographed on neutral alumina using chloroform-hexane (3:1, vzv) as the developing solvent. De-

tection by iodine V3PO I' shows two visible bands at R-f-0.6 and 0.4, respectively. Elution of the latter band with ethyl acetate, evaporation and crystallization gives an additional 126 mg. .of 3,17-bisethylenedioxy-4a,8,14-

- trimethyl-18-nor-5a,8a,1-4fl-androstane-1l-one. From the less polarband by rfollowingthe above procedure, 105 mg.

of 3,17-bisethylenedioxy-4a,8,14-trimethy1-1.8-nor-5a,8a,

13u,14fi-androstane-1l-one is obtained having a melting point about 215216 C., [0L122 -160". (chloroform), N552 5.91 my.

Analysis.-Calcd for C H O (418.55): C, 71.74; H, 9.15: Found: C, 71.68; H, 9.21.

Examples 16 to 18 Following the procedure of Example 15 but utilizing the reactants of Table C in lieu of 4a,8,14-trirnethyl-18- nor 5a,8a,14;8 androstane-3,11-17-tri0ne, the products formed are as indicated.

Example 1 9.-3 ,1 7-bisetlzylenedioxy-4 01,8,1 4 -trimethyl-1 8- n0r-5,8a,9fl,14,8-andr0szane-1 1 -one and 3,11,] 7-trisethylenedioxy 4a,8,14 trimethyl-l 8-n0r5a,8a,9fl,1 3a, 14,8-andr0stane A mixture of 400 mg. of 401,8,14-trimethyl-18-nor-5a, 8a,9fi,14B-androstane-3,11,17-trione, 100 ml. of dry benzene, 20 ml. of ethylene glycol and 40 mg. of p-toluene sultonic acid monohydrate is treated as described in Ex ample 15 and there are obtained 226 mg. of 3,17-bisethylenedioxy-4a,8,14-trimethyl-18-nor 5u,8a,9fi,14;8 androstane-ll-one and 37 mg. of 3,11,l7-trisethylenedioxy-4a,8, 14-trimethyl-18-n0r?5a,8u,9}8,13a,14fi-androstane having, a melting point about 235-237 C., [0:] 35 (chloroform).

Analysis.-Calcd for C H O (462.61): C, 70.10; H, 9.15. Found: C, 70.07; H, 9.13.

Example 20.3a-acet,0xy 17 ethylenedi0xy-4a,8,14-tri- Following the procedure of Example 15 but substituting 3a-acetoxy-4a,8,14-trimethyll'8-nor-5a,8a,9p,l4fi-androstane-11,17-dione for 4a,8,14-trimethyl-18-nor-5a,8a, 14 8-androstane-3,11,17-trione, there is obtained Sat-acetoxy-17-ethylenedioxy-4m,8,14-trimethyl-18-nor-5a,8a,9fl, l4fl-androstane-11-one, melting point about 137-139 C., [uh-14 (chloroform).

Analysis.-Calcd for C H O C, 71.74; H, 9.15. Found: C, 72.12; H, 8.74, and 3a-acetoxy-11,17-bisethyl enedioxy-4u,8,14-trimethy1-l8-nor-5a,8u,9 8,13a,14fl-androstane having a melting point 207- 21 3 C., [ab-2.0 (chloroform) Analysis.-Calcd for C H O (462.6): C, 70.10; H, 9.15. Found: C, 69.71; H, 8.96.

Example 21 .--4a,8,14-trimethyl-18-n0r-5a,8u,13a, 1 4 3-an drostane-3,1 1,1 7 -tri0ne A solution of 50 mg. of 3,17 bisethylenedioxy-4u,8,l4- trimethyl-l8-nor-5a,8a,13a,14,B-androstane-1l-one in 4.0 ml. of acetic acid is kept at room temperature overnight and then diluted with water. The mixture is extracted with chloroform which is Washed with water. and evaporated *in'vacuo. The residue (41.5 mg.) on crystal- 9 lization from acetone-hexane gives 33 mg. of 4oc,8,14-Uimethyl-18-nor-5a,8a,13a,I4fi-androstane 3,11,17 trione having a melting point about 170172 C. 275 (chloroform).

Analysis.-Calcd for C H O (330.45): C, 76.32; H, 9.15. Found: C, 76.40; H, 9.18.

Examples 22 to 35 When the procedure of Example 21 is substantially followed utilizing molar equivalents of the reactants in Table D in lieu of 3,17-bisethylenedioxy-4u,8,14-trimethyl-18-nor-5a,8a,1301,14fi androstane 11 one, the products indicated will be formed.

TABLE D Ex. Reactant "Product 22 3,17-bisethylene-llfi-hydroxy- 11 8-hydroxy-4a,8,14-trimethyl- 411,8,14-trimethyl-18-nor-5a, l8-nor-5a,8a,14fl-androstane- 8a,l4fl-androstane. 3,17-dine.

23 3B-acetoxy-11,17-bisethylene- 3B-acetoxy-4a,8,l4-trimethy1- 24 3a-acetoxy-17-ethylene-dioxy- 3u-acetoxy-lla-hydroxy- 11a-hydroxy-4u,8,14-tri- 4a,8,14-trimethyl-l8-nor- V methy1-18-nor-5a,8a,9fl,14B- a,8a,9;8,14B-androstane-17- androstane. one.

25 3fl-acetoxy-l7-ethylenedioxy- 3B-acetoxy-11a-hydr0xy- 11a-hydroxy-4u.8,14tri- 40:,8,14-trimethyl-18-n0rmethyl-l8-nor-5a,8a,9 3,1413- 5a,8a,96,14B-androstane-17- androstane. one.

404,8,14-trimethyl-18-nor-5a,

9(11)-en-17-0ne.

Following the procedure of Example 21 but substituting 3,11,17-trisethy1enedioxy 4a,8,l4-trimethyl-18-nor- '5a,8a,9 9,13a,14fl-androstane for the 3,17-bisethylened1- 1l-0ne, there is obtained 4a,8,14-trimethyl-18-nor 5u,8a,

9B,13a,14,3-androstane-3,11,17-trione, melting point 203- 205 C., [a] +3l-.4.

Example 3 7 -1 I ,B-hydroxy-4 01,8,1 4-trim ethyl-1 8-n0r- 5 u,8a,13a,14p-androstane-3,1 7 -di0ne Following the procedure of Example 21 but substituting 1lfi-hydroxy-3,l7-bisethylenedioxy 4u,8,14-trimethyl-1- nor-5a,8a,13a,14,8-androstane for the 3,17-bisethylened1- ll-one, there is obtained 11 8-hydroxy-4u,8,l4-trimethy1- 18-I10f-5cc,8o,13ot,14fl androstane 3,17-di0ne having a melting point about 206-208 C.

1 0 Example 38.4a,8,14-trimethyl-18-nor-5a,8a,I4/3- androst-9(11 -en-3,17-dione A solution of 51.7 mg. of 3,17-bisetbylenedioxy-4a,8, 14-trimethyl-l8-nor-5 a,8oc,14 3-and1OSt-9( 11)-ene in a mixture of 4 ml. of glacial acetic acid and 1 ml. of water is kept at room temperature for 16 hours, then slowly diluted with water. The crystals which separate are filtered, washed with water and dried to give 29 mg. of 404,8,14- trimethyl-18-nor-5a,8a,l4 androst-9(11)-en-3,17-dione having a melting point about ISO-182 C.

Following the procedure of Example 21 but substituting 3,17-bisethylenedioxy-4a,8,14 trimethyl l8-nOr-5oc, 8a,13u,l4;8-androst-9(11)-ene for the 3,17-bisethylenedioxy-4a,8,14-trimethyl-18-nor-5a,8a,13a,14fl androstanell-one, there is obtained 40,8,l4-trlmethyl-18-n0r-56z,8oc, 13a,14B-androst-9(ll)-en-3,l7 dione having a melting point about 156-157" C., [a] -156 (chloroform).

Example 40.4u,8,I4-trim ethyl-1 1 a-hydr0xy-18-n0r- 5 u,8a,9,8,14/3-androstan-3,1 7 -dione Following the procedure of Example 21 but substituting 11a-hydroxy-3,l7-bisethylenedioxy-4a,8,14-trimethyll8-nor-5a,8u,9fl,l4B-androstane for the 3,17-bisethylenedi0Xy-40z,8,14 trimethyl-l8 n0r-5oc,8cc,l3oc,14,8 androstane-ll-one, there is obtained 1la-hydroxy-4oz,8,l4-trimethyl-18-n0r-5a,8a,9 3,14,6-androstane-3,17-dione having a melting point about 181-183 C.

Following the procedure of Example 21 but substituting 3a-acetoXy-11,l7 bisethylenedioxy-4a,8,l4-trimethyl l8-nor-5a,8a,9 3,l3u,14fl-androstane for 3,17-bisethylendioxy-4a,8,14 trimethyl 18-I10r-5a,8a,13uc,14/3 androstane-ll-one, there is obtained 3a-acetoxy 4a,8,l4-tlimethyl-l8-nor-5a,8a,9fi,l3a,l4fi-androstane-l1,17 dione, melting point about 19920l C., [a];, -71 (chloro form).

Analysis.Calcd for C H O C, 73.76; H, 9.15. Found: C, 73.65; H, 19.14.

Example 42.3,I7-bisethylenedi0xy-11fl-hydr0xy-4u,8, 14-trimethyl-18-nor-5a,8a,14fl-andr0stane To a solution of 600 mg. of 3,l7-bisethylenedioxy-4oz,8, 14-trimethyl-l8-nor-5u,8a,14,6-androstane-1l-one in 50 ml. of tetrahydrofuran (freshly distilled from lithium aluminum hydride), 600 mg. of lithium aluminum hydride are added in portions over a five minute period and the suspension stirred at room temperature for 2.5 hours. The lithium aluminum hydride is then decomposed by the dropwise addition of methanol, the mixture diluted with water and extracted with chloroform. The chloroform is washed with water, evaporated in vacuo, and the residue crystallizedfrom acetone-hexane to give 547 mg. of 3,17- bisethylenedioxy-l 1fl-hydroxy-4u,8,14 trimethyl-lS-nor- 5oz,8u,14fi-androstane, having a melting point about 202- 204 C., [111 -60 (chloroform).

Analysis.Calcd for C H O (420.60): C, 71.39; H,

g 9.59. Found: C, 71.25; H, 9.76.

Examples 43 to 49 Substantially following the procedure of Example 42 but utilizing molar equivalents of the compounds indicated in Table E in lieu of 3,17-bisethylenedioxy-4a,8,l4- trimethyl-18-nor-5 a,8a,14fi-androstane-1l-one, the products shown will be obtained.

Example 5 0.-3 ,1 7-bisethylenedz'0xy-11 fi-hydroxy-4 a,8,1 4-

trimethy l-I 8-n0r-5 a,8ot,1 3 11,1 4 ,B-androstane Following the procedure of Example 42 but substituting 3,17-bisethylenedioxy-4a,8,14-trimethyl-18 nor 511,8oz, 13a,14fl-androstane-1l-one for 3,17-bisethylene-4a,8,14- trimethyl-18-nor-5a,8a,14,8-androstane-1l-one, there is obtained 3,17-bisethylenedioxy-llfi-hydroxy 404,8,14 trimethyl-l8-nor-5a,8a,13a,14B-androstane having a melting point about 211213 C., 66 (chloroform).

Analysis.Calcd for C H (420.57): C, 71.39; H, 9.59. Found: C, 71.77; H, 9.14.

Example 51 .1 1 a-hydroxy-SJ 7 bisethy lenedz'm-y- 4a,8,14-trimethyl-1 8-n0r-5a,8a,9 8,14fi-andr0stane Following the procedure of Example 42 but substituting 3,17 bisethylenedioxy-4a,8,14-trimethyl-18-nor-5a,8a,9fi, 14fl-androstane-11-one for the 3,17-bisethy1enedioxy-4a, 8,14-trimethyl-18-nor-5u,8a,14fi-androstane-1l-one, there is obtained 11a-hydroxy-3,17-bisethylenedioxy-4a,8,14 trimethyl-l8-nor-5a,8a,9fi,14fi-androstane having a melting point about 173-175 C., [011 82 (chloroform).

Analysis.Calcd for 0 11 0 (420.60): C, 71.39; H, 9.59. Found: C, 71.61; H, 9.39.

Example 5 2.] 1B-hydr0xy-4a,8,14-trimethyl-1 8-n0r- 5 0 802,] 4,8-androstane-3 ,1 7-di0ne A solution of 100 mg. of 3,17-bisethyl'enedioxy-1lp-hydroxy-4a,8,14-trimethyl-18-nor-5a,8 z,14fl-androstane in a mixture of m1. of methanol and 0.35 ml. of 8% sulfur'ic acid is refluxed for one hour, then partially evaporated and diluted with water. The crystals which sepa- 'rate are filtered, washed with water and dried to give 74 mg. of 11;8-hydroxy-4a,8,14=trimethyl l8-nor-5a,8u,14,8- androstane=3,17-dione having a melting point of 206- 208 C., +34 (chloroform).

AnalysiS.--Calcd for C H O (332.49): C, 75.86; H, 9.70. Found: C, 75.90; H, 9.75.

Following the procedure of Example 52 but substituting 3,17-bisethylenedioxy-1lfi-hydroxy 4a,8,14 trirnethyl- 18-n0r-5a,8a,l3a,14B-androstane for 3,17-bisethylene-1 1,8- hydroxy 40;,8,l4-trimethyl-l8-nor-5a,8 x,14B-androstane, there is obtained 11B-hydroxy-4u,8,l4fi-trimethyl-l8-nor- 5a,8a,14fl-androstane-3,17-dione.

To a solution of 274 mg. of 3,17-bisethylene-11p-hydroxy-4u,8,14-trimethyl-18-nor-5a,8a,143 androstane in 8.1 ml. of pyridine cooled to -20 C., 2.7 ml. of a solution of 100 mg. of thionyl chloride per milliliter of pyridine are added dropwise over a two minute period. The

solution is placed in an ice bath for 30 minutes and then carefully diluted with water. The crystals which separate are filtered, washed with Water and dried to ive 3,17'-bisethylenedioxy-4a,8,l4-trirnethyl-18-nor-5a,8a,14,3 androstane-9(11)-ene having a melting point about 106-108 C., [04 82", (chloroform).

Analysis.-Calcd for C H O (402.58): C, 74.59; H, 9.52. Found: C, 74.67; H, 9.54.

Examples 55 to 69 Following the procedure of Example 54 but utilizing the reactants of Table F in lieu of 3,17-bisethylenedioxy- 11 3-hydroxy-4u,8,14-trimethyl-l8 nor-5a,8u,l4fi androstane, the product of Table F will be obtained.

Example 7 0.-3,1 7-bisethylenedi0xy-4a,8,l4-trimethyl-18- nor-5a,8a,-13a,14fl-androst-9 (11 ene Following the procdure of Example 54 but substituting 3,17 bisethylenedioxy-l1fl-hydroxy-4a,8,14 trimethyl-l8- nor-5ot,8ot,13a,14fi-androstane for the 3,17-bisethy1ene'dioxy hydroxy 40:,8,14-trimethyl-18-nor-5a,8e,14,8- androstane, there is obtained 3,17-bisethylenedioxy-4a,8, 14-trimethyl-18-nore5a,8a,13a,14p-androst-9(11)-ene.having a melting point about 121-123 C.

Analysis.Calcd for C H O (330.45): C, 74.59; H, 9.52. Found: C, 74.43; H, 9.26.

Following the procedure of Example 54 but substituting 13 'stane-3,17-dione for 3 ,17-bisethylenedioxy-1lp-hydroxy- 411,8,14-trimethyl-18-nor-5a,8a,14 8-andr0stane, there is obtained 4a,8,14-trimethyl 18 nor 5 u,8u,14fl-androst-9 (11)-ene-3,17-dione.

Following the procedure of Example 54 but substituting 11,3 hydroxy-4a,8,14-trimethyl-l8-nor-5a,8,13a,14fl-androstane for 3.,17-bisethylenedioxy-1lfl-hydroxy-4a,8,l4- trimethyl-18-nor-5a,8a,14B-androstane, there is obtained 4a,8,14 trimethyl-18-nor-5u,8a,13a,14,B-androst 9(11)- ene-3,17-dione.

Example 73 .--3,1 7 -bisethylen'edi0xy-4 a,8,1 4-trim ethyl- 18-nOT-5a,8oc,14 3-zZHdrOSI-9 (I1 -ene Following the procedure of Example 54 but substituting 3,17-bisethylenedioxy-11a-hydroXy-4a, 8,14 trimethyl-l 8- nor-5a,8a,9fi,14/3-anclrostane for 3,17 bisethylenedioxy- 1lfl-hydroxy-4a,8,l4-trimethyl-18-n0r-5a,8oi,14/8 androstane, there is obtained 3,17-bisethylenedioxy-4a,8,14- trimethyl- 1 8-110r-5a,8oc, 14p-androst-9( l1)-ene.

Example 74.-4a,8,14-trimethyl-18-nor-5a,8a,14 3-andrst-9(1 1 )-ene Following the procedure of Example 54 but substituting 11a-hydroxy-4a,8,l4-trimethyl-18-nor u,8a,9;9,14fi-androstane-3,17-dione for 3,17 bisethylenedioxy llfi-hydroxy-4u,8,14-trimethyl 18-n0r 5a,8a,14fi androstane, there is obtained 4a,8,14-trirnethyl-l8-nor-5a,8a-14 3-androst-9(11)-ene.

Example 75 .-3 a-acetOxy-I 7 -ethylenedi0xy 4a,8,14 trimethyl-18-n0r-5a,8a,14fl-androstane 11 one and 3 aacetoxyJ 7-ethylenedi0xy-4a,8,14-trimethyl 18 nor- 5 a,8a,1 3 11,1 4fl-andr0stane-1 1-0ne Following the procedure of Example 15 but substituting 3a-acetoxy-4a,8,14-trimethyl-l8 nor 5oz,8a,l4fi-androstane-ll,17-dione for 4o 8,14-trimethyl-18-nor-5u,8u,l4fiandrostane-3,l1,17-trione, there is obtained 3a-acetoxy- 17-ethylenedioxy-4a,8,14-trimethyl-18 nor 501,841,145- androstane-ll-one having a melting point about l65l67 C., [a1 145 C. (chloroform).

Analysis.Calcd for c25H3305I C, H, 9.15- Fo-und: C, 71.50; H, 9.21.

In addition, there is obtained 3a-acetoxy-17-ethylenedioxy-.4a,8;14-trimethyl-18 nor 5a,8a,130t,14]3 androstane-ll-one having a melting point about 185l87 C.

What is claimed is:

1. A compound having the formula CH: H

l ru wherein C is selected from the group consisting of C=O C :l and C11 o c and O-acyl 0 O-aeyl is selected from the group consisting of C=O and wherein the acyl is a hydrocarbon carboxylic acid of less than twelve carbons.

2. 11u-hydroxy-4a,8,14-trime-thyl-18-nor-5a,8a,9fl,145'- androstane-3,17-dione.

14 3. 11fi-hydroxy-4u,8,14-trimethyl-18-nor-5u,8u,14,8-androstane-3,17-dione. i

4. 11fi-hydroxy-4a,8,14-trimethyl-18-nor-5a,8a,13u,14fiandrostane-3,l7-dione.

5. A compound having the formula 16. A compound having the formula 17. 17-ethylenedioxy 312,11fi dihydroxy 4a,8,14-trimethyl-18-nor-5u,8a,13a,14fl-androstane.

18. l7-ethylenedioxy 313,113 dihydroxy 4a,8,14-L1imethy1-18-nor-5a,8a, 13a, 14,3-androstane.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,352,854 November 14, 1967 Patrick A. Diassi et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 28 to 31, for

/H /H C read C O-aeyl *O-acyl column 2, line 29, for "deactoxylating" read deacetoxylating column 5, lines 35 to 44, formula V should appear as shown below instead of as in the patent:

same column 5, lines 64 to 66, for

R is C :I read R is C column 6, line 20, for "3a," read 3B, line 21, for "136," read 13a, column 12, line 63, for "procdure" read procedure column 14, lines 20 to 23, for

0 read Signed and sealed this llth day of March 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND HAVING THE FORMULA 